The present invention provides a process for the preparation of Meropenem.
(4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxy-ethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid as represented by Formula I, commonly known as meropenem, is synthetic, broad-spectrum, carbapenem antibiotic. (Formula Removed)
FORMULA I
US Patent No. 4,943,569 provides a process for the preparation of meropenem, which involves the reaction of enolphosphate of Formula II,
(Formula Removed)
FORMULA II
with a thiol side chain of Formula III in the presence of diisopropylethylamine,
(Formula Removed)
FORMULA III
to obtain a protected meropenem of Formula IV, which is subsequently purified by silica gel thin layer chromatography.

(Formula Removed)
FORMULA IV
The purified compound of Formula IV is then dissolved in a mixture of tetrahydrofuran and ethanol, and the mixture is hydrogenated in a morpholinopropanesulfonic acid buffer solution in the presence of palladium catalyst. After filtering off the catalyst, the organic layer is distilled off and meropenem is isolated from the aqueous layer by polymer chromatography. J. Antibiot. (Tokyo), 1990, 43(5), 519-532 provides a similar process, wherein the final product is isolated by column chromatography and subjected to lyophilization to get amorphous meropenem.
US Patent No. 4,888,344 also provides a process for preparing meropenem, wherein the compound of Formula IV is dissolved in a mixture of tetrahydrofuran and ethanol, and the mixture is hydrogenated in the presence of palladium catalyst. After removing the catalyst by filtration, the filtrate is washed with water and tetrahydrofuran is distilled out; the residue is subsequently washed with dichloromethane and again subjected to distillation under reduced pressure to remove the organic solvent, whereby an aqueous solution of the crude product is obtained. This aqueous solution is concentrated by reverse osmosis, and the crystals of meropenem trihydrate are precipitated out by the addition of tetrahydrofuran under stirring.
WO 06/035300 provides a one pot process for the preparation of meropenem. The said process involves hydrogenation of the compound of Formula IV in a biphasic reaction mixture, separation and isolation of meropenem trihydrate by the addition of acetone.
The present inventors have developed an advantageous process for the preparation of meropenem, wherein the entire process is carried out in one pot in a monophasic reaction medium. The present process avoids isolation and purification of the compound of Formula IV. The present process, thus, does not require layer separation, solvent recovery, extraction, reverse osmosis, chromatographic purification or lyophilization. The present invention also provides a means for isolating crystalline meropenem with a purity of about 98% or more, directly from a homogeneous reaction mixture, without employing any specialized purification methods. Thus, the present invention provides an economic and industrially preferable process for the preparation of meropenem.
The term "protecting group" in the present invention refers to those used in the art and serve the function of blocking the carboxyl, amino or hydroxyl groups while the reactions are carried out at other sites of the molecule. Examples of a carboxyl protecting group include, but not limited to, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 alkenyl, optionally substituted C7-C19 aralkyl, optionally substituted C6-C12 aryl, optionally substituted C1-C12 amino, optionally substituted C3-C12 hydrocarbonated silyl, optionally substituted C3-C12 hydrocarbonated stannyl, and a pharmaceutically active ester forming group. Examples of hydroxyl and amino protecting groups include, but not limited to, lower alkylsilyl groups, lower alkoxymethyl groups, aralkyl groups, acyl groups, lower alkoxycarbonyl groups, alkenyloxycarbonyl groups and aralkyloxycarbonyl groups.
A first aspect of the present invention provides a process for the preparation of meropenem of Formula I,
(Formula Removed)
FORMULA I
wherein the said process comprises, a) reacting the compound of Formula III
(Formula Removed)
FORMULA III wherein PI represents an amino protecting group, with a compound of Formula II,
(Formula Removed)
FORMULA II
wherein P2 represents a carboxyl protecting group, P3 represents hydrogen or a hydroxyl protecting group, and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyi or aryl, to get the compound of Formula IV,

(Formula Removed)
FORMULA IV
wherein P1, P2 and P3 are as defined above,
b) deprotecting the compound of Formula IV in a monophasic reaction medium, and
c) isolating meropenem from the reaction mass thereof,
wherein the compound of Formula IV is not isolated from the reaction mixture.

Enolphosphate of Formula II and thiol side chain of Formula III can be prepared by the processes reported in the prior-art as mentioned earlier. Enolphosphate is dissolved in
a water miscible organic solvent and cooled to a temperature of about 0°C or less. The water miscible organic solvent is selected from a group comprising of tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile, N-methyl-2-pyrrolidone, acetone, and dioxane. The water miscible organic solvent is preferably selected from a group comprising of dimethylformamide, N-methyl-2-pyrrolidone and tetrahydrofuran. Thiol side chain is added to the reaction mixture at the same temperature conditions and stirred in the presence of a base for sufficient time to effect the coupling reaction. A secondary amine or a tertiary amine can be used as a base. The base is preferably diisopropylethylamine or diisopropylamine. The reaction mixture is subsequently hydrogenated using a palladium catalyst without isolating the protected intermediate of Formula IV. The hydrogenation is preferably carried out in the presence of a non nucleophilic buffer. The non nucleophilic buffer is selected from a group comprising of morpholinopropanesulphonic acid, morpholinoethanesulphonic acid or an aqueous buffer comprising N-methylmorpholine. The reaction medium is maintained monophasic during the hydrogenation process. After completion of the hydrogenation, the reaction mixture is filtered to remove the catalyst and crystalline meropenem can be isolated directly from the homogeneous reaction mixture. The isolation of crystalline meropenem can be carried out by the addition of an excess of water miscible organic solvent to the reaction mixture and cooling at a temperature of about 10°C or less.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLE 1
PREPARATION OF MEROPENEM:
(Formula Removed)
Enolphosphate of Formula II (50 g) was dissolved in N,N-dimethylformamide (250 ml) and cooled to -30° to -25°C. The thiol side chain of Formula III (30 g) was added to the reaction mixture followed by drop-wise addition of diisopropylethylamine (14.1 g) at -30° to -25°C. The reaction mixture was stirred at -30° to -25°C for 2 h to obtain the compound of Formula IV. The formation of the product was monitored by thin layer chromatography. 5% Palladium-carbon (50 g) was added to a buffer containing N-methylmorpholine (25.5 g) and appropriate quantity of hydrochloric acid so as to obtain a pH of 6.5 to 7.0 in distilled water (500 ml). The reaction mixture containing the compound of Formula IV was added to the buffer and hydrogenated for 3 to 4 h at about 25°C. The catalyst was filtered after the completion of hydrogenation and washed with water (100 ml). The filtrate was cooled to 0°-5°C and acetone (4 L) was added to the filtrate. The reaction mixture was stirred for 6 h at 0°-5°C and the product
so obtained was filtered, and washed with acetone to obtain the title compound in crystalline form.
Yield: 18 g
Purity: 98% (HPLC)
EXAMPLE 2
PREPARATION OF MEROPENEM:
Enolphosphate of Formula II (20 g) was dissolved in N-methyl-2-pyrrolidone (100 ml) and cooled to -20° to -15°C. The thiol side chain of Formula III (12 g) was added to the reaction mixture followed by the drop-wise addition of diisopropylethylamine (5.6 g) at -15° to -5°C and the reaction mixture was stirred to obtain the compound of Formula IV. The formation of the product was monitored by thin layer chromatography. 5% Palladium-carbon (30 g) was added to a buffer containing N-methylmorpholine (3.4 g) and appropriate quantity of hydrochloric acid so as to obtain a pH of 6.5 to 7.0 in distilled water (120 ml). The reaction mixture containing the compound of Formula IV was added to the buffer and hydrogenated for 3 to 4 h at about 25°C. The catalyst was filtered after the completion of hydrogenation and washed with water (100 ml). The filtrate was treated with activated charcoal and acetone (1.6 L) was added to the filtrate at 0°-5°C. The reaction mixture was stirred for 6 h at 0°-5°C and the title compound is isolated in crystalline form by filtration.
Yield: 6.0 g Purity: 98% (HPLC)

WE CLAIM:
1. A process for the preparation of meropenem of Formula I,
(Formula Removed)
FORMULA I
wherein the said process comprises, a) reacting the compound of Formula III (Formula Removed)
FORMULA III
wherein P1 represents an amino protecting group, with a compound of Formula II, (Formula Removed)
FORMULA II
wherein P2 represents a carboxyl protecting group, P3 represents hydrogen or a hydroxyl protecting group, and X represents OP(0)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl, to get the compound of Formula IV,
(Formula Removed)
FORMULA IV
wherein PI, P2 and P3 are as defined above,
b) deprotecting the compound of Formula IV in a monophasic reaction medium, and
c) isolating meropenem from the reaction mass thereof,
wherein the compound of Formula IV is not isolated from the reaction mixture.

2. A process as claimed in claim 1, wherein the monophasic reaction medium
comprises a water miscible organic solvent.

3. A process as claimed in claim 2, wherein the water miscible organic solvent is
selected from a group comprising of tetrahydrofuran, dimethylformamide,
dimethylsulfoxide, acetonitrile, N-methyl-2-pyrrolidone, acetone, C1-3 alcohol, and
dioxane.

4. A process as claimed in claim 3, wherein the water miscible organic solvent is
selected from a group comprising of dimethylformamide, N-methyl-2-pyrrolidone and
tetrahydrofuran.

5. A process as claimed in claim 1, wherein step b) is carried out in the presence of a
non nucleophilic buffer.

6. A process as claimed in claim 5, wherein the non nucleophilic buffer comprises morpholinopropanesulphonic acid, morpholinoethanesulphonic acid or an aqueous buffer comprising N-methylmorpholine.
7. A process as claimed in claim 1, wherein step a) is carried out in the presence of a
base.
8. A process as claimed in claim 7, wherein the base is a secondary amine or a
tertiary amine.
9. A process as claimed in claim 8, wherein the base is diisopropylethylamine or
diisopropylamine.
10. A process as claimed in claim 1, wherein step b) is carried out in the presence of a
palladium catalyst.